PUBERTY BLUES

Boys’ voices are breaking earlier; girls are developing breasts as young as six. But why? Fiona Neill meets the Danish scientists who are on the case …

From INTELLIGENT LIFE Magazine, Summer 2010

In December 2003 a story appeared in the Copenhagen newspaper MetroXpress. It spoke of crisis at the world-famous Copenhagen Municipal Choir School. For the first time since its founding in 1924, the Copenhagen Royal Chapel Choir was having trouble finding enough 12- and 13-year-old boys to send on its annual American tour.

The trip was the culmination of years of training for these young Danish boys, who had been picked out to attend the school when they were eight. The problem was simple but insurmountable: the boys’ voices were breaking younger. The choir required trebles. But the trebles were turning into tenors and instead of a full tour of the United States they had to make do with a whistle-stop tour to Estonia with an adult choir.

The story might have been forgotten had it not come to the notice of Professor Niels Skakkebaek, then head of the department of growth and reproduction at Copenhagen University Hospital. For Skakkebaek it represented an opportunity. His team of paediatric endocrinologists—specialists in glands and hormones—had noticed an alarming increase in the number of children being referred with symptoms of early puberty. The choir story resonated with what they were seeing.

They had seen a surge in the number of young girls showing signs of breast development, some as young as six. They wanted to know if there was a connection between what they were seeing in clinic and what was happening at the choir school. In 1997 researchers had begun pointing to a dramatic decline in the age of puberty in America. Was the same thing now happening in Europe?

Skakkebaek’s department, founded 20 years ago, now occupies the two top floors on the west side of Copenhagen University Hospital. Compared with the children’s ward just across the hallway, it is an oasis of restraint. Researchers wearing white lab coats wander into the corridor, occasionally opening huge chest freezers in search of test-tube samples. In a meeting room a group of scientists discuss a recent research paper on male sperm count. Just opposite, a child involved in a research project lies on a bed having blood tests.

Skakkebaek, now in his 70s, has handed the reins to Anders Juul, a flamboyant, tousle-haired endocrinologist. “We used to think early puberty was an American problem,” Juul tells me, “to do with American lifestyle, hormone-treated beef, obesity, too much sitting around watching TV and playing on the internet. We felt we should repeat studies that we had done in 1991, which showed no change in the age of puberty, to see if we were now experiencing this phenomenon.”

The last 200 years have seen a big drop in the age of puberty in the West. In the Leipzig choir directed by J.S. Bach in the 1700s, the average age of voice break, a late marker of male puberty, was around 18. Between the mid-19th and mid-20th century, the average age for girls having their first period in America and northern Europe dropped from 17 to under 14.

At first glance it might seem an evolutionary contradiction that as the average age of marriage was rising, the age of sexual maturity was falling. But this trend has its own logic: human beings reproduce when they are healthy. As nutrition and health care improved, the age of puberty dropped. From 1950 onwards the age of puberty plateaued.

In 1950 a British paediatrician, Dr James Tanner, introduced a system for mapping the five stages of puberty in boys and girls. Drawing on two decades of research in a children’s home in Hertfordshire, Tanner concluded that the average age of breast development, often the first sign of puberty among girls, was 11.5 years. Among boys puberty, defined as an increase in testicular volume, began at around 11.2 years. The Tanner scale became a benchmark around the world.

In 1997, however, a group of American researchers published a study of 17,000 girls that showed a sudden lurch in the age of puberty. Its author, Professor Marcia Herman-Giddens, found the average age of puberty among white girls had dropped to 9.7 years. Among Afro-Americans, the trend was even more pronounced: girls were hitting puberty at eight. Some were getting there at six, just a year after starting school. The results were controversial. There were questions over methodology: the girls had attended doctors’ surgeries and were therefore not representative of the wider community; researchers hadn’t examined the girls properly, relying on visual evidence of breast development rather than a physical examination. Many of the girls were obese and might have looked as though they were developing breasts when in fact they were simply fat. But then in 2002 a second study revealed similar results. Breast development seemed to be happening between one and two years earlier than Tanner had indicated.

And if breast development was occurring earlier, girls would inevitably get their period earlier. Herman-Giddens suggested that the Tanner scale should be revised in America.

These findings shocked the endocrinology community and set off a new wave of research. So when Skakkebaek and his team saw the news about the choirboys they contacted the Royal Chapel Choir. To their delight, they were told that the school had kept meticulous records of children’s height and weight, and made weekly voice assessments to record any unintentional falsettos. Parents and children were happy for these to be used in the name of research and the results were published in 2006.

“We discovered that over a ten-year period boys’ voices were breaking around four months earlier,” Juul says, surrounded by precarious stacks of research papers and medical journals in his office. “And that the heavier the boy at eight years old, the earlier the age of voice break.”

Another member of the department, Dr Lise Aksglaede, began investigating the age of breast development among Danish girls. Aksglaede has a calm exterior, and behind it, plenty of tenacity: she managed to persuade the parents and teachers of almost a thousand schoolgirls to sign up to her project. The results, published last May, the first of their kind in western Europe, showed that over 15 years the age of breast development in Denmark had dropped a year, from 10.8 years in 1991 to 9.8 years in 2006. They were also having their first periods, on average, three months earlier.

“It would have been significant if we had simply reported that menarche [the first bleeding] was occurring three months earlier in such a short period of time,” Aksglaede says, “but the fact that breast development was occurring a year early is a remarkable change. Something is going on at a population level, something visible is happening right now. In 15 years’ time, will girls be growing breasts two years earlier? It’s extremely worrying because we don’t know why it’s happening.”

In January, the department published a further study of Danish boys. It showed that the age of puberty had dropped by three and a half months over 15 years, reinforcing the results of the choirboy study. In China a study last year reported the lowest-ever average age for breast development, 9.2 years. Dutch and Italian studies have also echoed what the Danes have discovered among boys.

The term puberty comes from the Latin word puberatum, meaning age of maturity. In the past puberty (the process of sexual maturation) and adolescence (the process of psychological development) occurred in tandem. The decoupling of these processes means that the gulf between physical and psychological maturity has never been greater.

Dr Richard Stanhope, a leading British paediatric endocrinologist who has spent 24 years at Great Ormond Street Hospital for Children, believes this presents dramatic challenges. He feels that children who go into early puberty are prematurely sexualised and too immature to deal with the implications. They are more vulnerable to sexual abuse, inappropriate sexual behaviour, sexually transmitted diseases and teenage pregnancy. “It means that children develop sexually much earlier,” Stanhope says. “They are physically ready for sexual reproduction but mentally completely unready.”

Studies have shown that adolescents who go through puberty earlier are involved in more risk-taking behaviour, such as taking drugs, binge drinking and breaking the law. A premature increase in testosterone can lead to aggression in boys who lack the maturity to control impulses. “We all realise that testosterone is a very difficult hormone to learn to live with,” Stanhope says, tapping a pencil vigorously on his pockmarked table, “and if you get a rise in testosterone outside the normal physiological age, then it’s even more of a problem.”

Research published this year in the Australian and New Zealand Journal of Criminology also found increased aggression in girls who reached puberty early. In Britain the uncomfortable reality that children are becoming sexually mature earlier has been overlooked in the recent debate about the over-sexualisation of children. Instead of simply focusing on cynical manufacturers producing padded bras for seven-year-olds, perhaps we should also consider how to respond to the new reality that some girls are now growing breasts at this age.

Stanhope also points out that for women there may be long-term health problems, because early puberty increases exposure to oestrogen. According to Cancer Research UK, a girl who has her first period a year later than her contemporaries has 5% less risk of developing breast cancer in later life. “There may be an important link with breast and ovarian cancer,” Stanhope says. “The earlier a girl has her period, the longer her exposure to oestrogen and this may well have very important sequelae for oestrogen-dependent tumours. This increases her risk of breast cancer, ovarian cancer and of developing cardiovascular problems.”

Girls who reach puberty early are also more likely to develop type 2 diabetes. A 37-year-long study of 61,000 Norwegian women showed that women who got their first period at ten or 11 had a 10% higher mortality rate than those who got their period four years later.

The long-term risks for men are less proven. Stanhope believes research should focus on whether there is a link between early puberty in boys and prostate cancer. He also points out that although early puberty is becoming more common, it still isn’t the norm, and anything that marks children out from their peer group makes life more difficult.

Hayley Smith, who is 14, knows exactly what he is talking about. She started developing breasts when she was five. A year later, when still at infant school, she had her first period. She was dealing with monthly mood swings, stomach cramp, migraines and spots at the same time as learning to read and write. Every month she missed three or four days of school.

Girls have a growth spurt that slows down with the onset of their first period (for boys, weight and height come in the final stages of puberty). So at six years old, Hayley towered over her classmates. Her school uniform had to be handmade and her feet were already size two. Although her school and friends were supportive, she says she was bullied by some children. She also found herself ostracised by their parents, who were perhaps unnerved by this young child imprisoned in an adolescent body.

“They told their children not to hang around with me,” Hayley says. “It was very hurtful. I just wanted to be the same as my friends and I felt left out. Sometimes I didn’t want to go to school.”

Hayley was fortunate in that her mother Debbie, an articulate and resourceful NHS administrator, quickly grasped what was happening. She bought Hayley picture books to explain the changes in her body, spoke to the parents of children who were bullying her, made sure the school understood the situation and fought for a diagnosis with disbelieving doctors. “It was awful,” Debbie says. “There was so much ignorance. People treated her differently—Hayley didn’t really have a childhood. You just don’t expect to have to talk to your six-year-old daughter about having periods.” Debbie also confronted prejudices close to home: one family member suggested Hayley’s early puberty had been caused by sexual abuse.

The evidence from Denmark suggests that Hayley’s experience could soon be commonplace. Most paediatric endocrinologists now agree that the age of puberty is falling fast in developed nations. But there is no consensus on why. The changes are happening too fast to be genetic, so the focus is on environmental factors. Obesity, chemicals and even absentee fathers have all been investigated (a girl who lives apart from her father tends to get her period earlier).

In Britain there is very little contemporary data on the age of puberty, although all the paediatric endocrinologists I interviewed reported seeing more referrals to their clinics. This is in part because a standardised system for monitoring weight and height was only introduced in 2006. It is also due to the fact that the British are more squeamish than the Danes about their children being examined.

It is intrusive. Girls have to be physically examined to see if breast buds have appeared, and boys’ testicular volume has to be measured and recorded.

“The Danes are a very curious population in that when they do their studies, parents and children are happy for investigators to do hands-on investigations,” says Dr Ken Ong, a researcher in the Medical Research Council epidemiology unit at Addenbrookes hospital in Cambridge. “We have tried to persuade parents to let their children do this in the UK but they ran a mile.” Instead British researchers have to rely on asking adult women to remember the date of their first period, something most women are able to recall accurately. It is a more exact science than asking a man when his voice broke or he had his first wet dream.

Puberty also remains a mysterious process: no one fully understands how it happens. Scientists know that it can’t start until the hypothalamic pituitary-gonadal axis is activated in the brain. They are also certain that this complex endocrine glandular junction plays a critical role in sexual development and reproduction by sending messages from the hypothalamus, through the pituitary gland, to release sex hormones, including oestrogen and testosterone.

One certainty is that it doesn’t occur until children hit a critical body weight. Anorexic girls seldom get pregnant. (In impoverished regions of China and Senegal where malnutrition is still a problem, studies have shown that the average age of a girl’s first period remains around 16.) Once a critical body mass has been reached, a hormone called Leptin is produced. It is secreted from fat tissue in direct proportion to the amount of total fat mass: the fatter a child, the more Leptin they produce. This sends signals to the hypothalamus and plays a role in triggering the neurotransmitters that stimulate puberty.

Scientists have identified two neurotransmitters, NPY and PYY, that are linked to the reproductive system. They regulate appetite, which may explain why the fridge is never full enough when children hit adolescence. In the past two years, scientists have also uncovered other neurotransmitters called kisspeptins (so called because they are products encoded by the kiss-1 gene) that are believed to trigger puberty, but as yet there is no proven link between them and NPY and PYY.

Since the American study of 1997 raised the spectre of a connection between weight and early puberty, scientists have become convinced that there is at least some link with the obesity epidemic. The two trends have developed in parallel, and the Danish choirboys who didn’t make it to America because their voices had broken were heavier than those who did. Another Danish study published last year showed that the heavier children were at seven, the earlier they entered puberty.

Ken Ong and his team are investigating the relationship between early puberty and specific genetic variants that can cause obesity. Using blood collected from thousands of women in Norfolk in the 1990s, they have shown a correlation between increased body mass and early puberty. They have also discovered that women with any of the obesity genes are also more likely to enter puberty prematurely. “The obesity variants confer earlier menarche,” Ong says, choosing his words carefully. “From this we can infer that childhood obesity does have a causal influence on earlier puberty.” Their latest research suggests that the more weight a baby girl gains in the first year of life, the earlier her first period starts. In Britain, where one ten-year-old in six is now obese and a further one in six is overweight, this could have the same dramatic impact that was reported in America in 1997.

But obesity alone doesn’t fully explain the decline. Having outlined all his research, Ong points out, in an equally cautious tone, that it could also be that early puberty triggers obesity. The Danish schoolgirls who participated in Aksglaede’s research were heavier than they might have been a couple of decades ago, but there was no difference between the Body Mass Index of the girls who were growing breasts a year earlier and that of those who weren’t.

As she leads me around the labs at the top of the National University Hospital, Aksglaede says: “We couldn’t relate the changes to obesity.” Scientists wearing goggles and lab coats look up as we come in. Some are working on machines to extract DNA from samples, others measuring hormones in samples. “This doesn’t mean that obesity isn’t important…but it doesn’t explain the trend. Obesity is an important risk factor.” The Danish team is hoping that the research taking place here might help at least to widen the debate.

In a small room smelling strongly of bleach, a machine known as a Triple Mass Spectrometer whirrs away. At one end of it tiny test-tubes of blood belonging to these same Danish schoolgirls are lined up. Each sample is put through the machine in order to separate seven different chemical compounds called phthalates. The same process also takes place with urine samples from the girls.

The compounds under the spotlight are all Endocrine Disrupting Chemicals (EDCs), mostly man-made, and believed to have a corrosive influence on the way hormones work in our bodies. According to Anders Juul, most EDCs either mimic sex hormones, oestrogens in females and androgens in males, or interfere with the way they are metabolised. He believes they may be responsible for influencing when puberty starts and how it progresses.

Above the noise, the senior chemist, Hanne Frederiksen, explains that once the phthalates have been separated from each sample, they will see if there are higher levels of these hormone disruptors in the girls who are growing breasts earlier.

“My instinct is that EDCs are involved in early breast development,” says Juul. “It’s more of a gut feeling than anything else…We don’t have any strong evidence as yet, but I think it’s a sound hypothesis that needs to be proven or disproven. We need to consider what has changed in the environment over the past 15 years. It would be fantastic to know we were wrong and that EDCs are not involved in early puberty.”

It’s already known that some phthalates mimic oestrogen. For girls oestrogen is one of the main reproductive hormones, and it is implicated in breast development. It is a heavy hitter: tiny amounts can have big consequences in children, who should have very little of it until they hit adolescence. In chromosomal disorders such as Turner Syndrome, girls are given a type of oestrogen called oestrodial to induce breast development. “Children are extremely sensitive to hormones before puberty,” says Skakkebaek, “because they are producing so little that small amounts can make a difference.”

Skakkebaek is somewhat of a legend among endocrinologists, for his pioneering work on testicular cancer in the 1970s and subsequent research into the alarming fall in male fertility in Europe and America. He was also one of the first scientists to suggest that chemicals could imitate hormones and to warn of the dangers of this chemical deception.

The debate over EDCs is mired in controversy, akin to the debate over global warming, with environmentalists on one side, big business on the other, and scientists caught in the middle. It is a particularly tricky area of research because we are all now exposed to a cocktail of EDCs in our daily life. This makes it hard to measure how any individual compound might affect the endocrine system. It is almost impossible to measure individual exposure. And it’s likely that this chemical cocktail is passed from mother to baby in the womb.

The adverse effects of oestrogenic pollutants have been known since the early 1990s, when Professor John Sumpter, a fish physiologist at Brunel University, reported an outbreak of hermaphrodite fish in rivers in England. Male fish were found to be developing smaller testes and were producing the female yolk protein found in eggs, so they were becoming feminised. The results of his investigations led Sumpter to suspect that man-made industrial chemicals in sewage effluent were acting as female oestrogens.

Natural oestrogens, known as phyto-oestrogens, are also present in many plants, including soya. But just because they are natural doesn’t mean they are benign. In 2007 a study in the New England Journal of Medicine described how three young boys began growing breasts after using products containing lavender and tea-tree oils. In one case a mother used a healing balm containing lavender oil on her four-year-old son; in another a ten-year-old boy used hair gel containing lavender and tea-tree oil; in the final example a seven-year-old was using lavender soap. Lavender and tea-tree were found to cause hormonal disruptions by mimicking oestrogen. When they stopped using lavender and tea-tree, the boys’ chests returned to normal. This was the first time the relationship between EDCs and hormonal disruption in human beings had been proven.

If you were to do a line-up of the key suspects, Skakkebaek says, phthalates like the seven being tested in the laboratory would come first. These are substances that are added to plastics to increase their flexibility, transparency and durability. A few have already been phased out of products in America and Europe over health concerns. But the phthalates that make plastic flexible are still found in anything from cellophane to shower curtains to toys, and they are omnipresent in food packaging. Despite extensive research, their effects on humans are still poorly understood.

The next suspect would be Bisphenol A, a component of polycarbonate found in the lining of tin cans, children’s feeding cups and in plastic bottles, including baby bottles. Later this year the urine and blood samples from the Danish puberty study will be tested for this chemical. Skakkabaek points out that animal experiments have shown that Bisphenol A is a weak oestrogen that can accelerate pubertal development in mice. But there is still controversy over whether neonatal exposure can trigger early puberty. Last year the Danish government passed a motion to prevent the use of Bisphenol A in milk bottles, but it has yet to be enacted. In 2008 Canada followed suit. In January the US Food and Drug Administration recommended a similar ban on Bisphenol A in baby bottles and infant feeding cups because of “concern about the potential effects of BPA on the brain, behaviour and prostate gland in fetuses, infants and young children,” based on recent studies using “novel approaches to test for subtle effects”.

Skakkabaek says that scientists first detected the oestrogenic potential of Bisphenol A almost 60 years ago, when they were trying to produce a synthetic oestrogen to prevent miscarriages. Bisphenol A was rejected in favour of a stronger oestrogen, Diethylstilbestrol (DES). This was widely used in the 1950s until it was discovered that many women who had taken DES had gone on to develop vaginal cancer and had passed that risk on to their daughters.

“In spite of the fact we have known that Bisphenol A was a weak oestrogen, it was considered safe enough to use in polycarbonate in plastic,” Skakkabaek says. “It is also a fact that some of the molecules can leak into milk in baby bottles. So the controversy is whether it’s harmful for a baby to drink from it. This is difficult to establish because the effects may not be evident for many years and we are all exposed to a complex cocktail of tiny amounts of other chemicals which may act together or be antagonistic.”

Then there are parabens, preservatives used in many everyday products including sun lotion, shampoo and deodorant; and finally the phyto-oestrogens, like lavender, fennel and tea-tree, and perhaps most significantly, given its widespread use in America, genistein in soya. American children have a particularly high exposure to EDCs, Skakkabaek says, because 80% of American beef is still treated with growth promoters. In most cases a tag containing a mix of natural sex hormones (a combination of oestrogen, testosterone or progesterone) and synthetic hormones (zerinol, trenbolone and melengestrol) is implanted as a pellet in the ear of beef cattle in order to get the calves to grow and gain weight faster.

“You have to consider the possibility”, he says, “that exposure of children to sex hormone residuals still present in beef at slaughter could contribute to the reduced age of puberty in American children.” European nations were sufficiently concerned about hormone residues to ban the use of growth promoters decades ago. American beef that is produced using these anabolic sex hormones has been banned since 1989.

The research continues. We know little about how the human body copes with the chemicals that have inveigled their way into our daily life. The Danish study, to be published next year, should leave us the wiser about the role they play in turning our children into adults before their time.

(Fiona Neill is a novelist and a regular contributor to the Times magazine.)